In the modern era, there are several retrospective data that demonstrate the beneficial role of cytoreductive nephrectomy. In two such studies, there was more than a 10 months survival advantage with cytoreductive nephrectomy conferring an HR of 0.6-0.68 for improving overall survival.3,4 In a national cancer database study, cytoreductive nephrectomy conferred an HR of 0.62 for overall survival. 5
The CARMENA trial, which was a phase 3 randomized study comparing nephrectomy plus Sunitinib vs. Sunitinib alone in first-line metastatic RCC.6 This trial clearly showed no difference between both arms in overall survival. However, this trial had some significant limitations including poor accrual, predominantly intermediate / poor risk patients, off-protocol treatments, sunitinib no longer standard of care, and Motzer criteria not optimized for selection of surgical candidates.
The first major problem is poor accrual. The target recruitment was 576 patients with 12 patients per month for 4 years. However, after 8 years, only 450 patients were accrued with a rate of 0.7 patients/site/year which is strikingly low. Just as an example, in Norway, who had centers that were part of the trial, there are 600 new metastatic RCC patients each year. However, only 10 patients were accrued for the CARMENA study in the trial period. In general, trial participants have been shown to harbor much more aggressive disease than non-participants, with a higher rate of metastases, and more poorly differentiated tumors.7
The second major problem of CARMENA was the high rate of poor risk patients that were included. The trial was obviously skewed towards higher risk patients. Over 40% of patients were poor risk, with a high metastatic burden.
The third problem with CARMENA was the amount of off-protocol treatments. In the nephrectomy group 7.1% of the nephrectomy patients did not actually undergo nephrectomy, and 17.7% did not actually receive sunitinib. Moreover, in the sunitinib group, 4.9% never received sunitinib, and 17% underwent nephrectomy.
The fourth problem is that sunitinib is now regarded as suboptimal medical treatment. The Checkmate 214 study demonstrated a clear advantage of immunotherapy and angiogenesis inhibitor combination over sunitinib and other newer trials showed similar results.
The fifth problem is that Motzer criteria were developed to predict survival among metastatic RCC patients, and not to predict who would benefit from cytoreductive nephrectomy. There are other existing prognostic models that can predict the benefit from performing cytoreductive nephrectomy.
In summary, the properly selected patients for cytoreductive nephrectomy should be the ones with no untreated brain metastasis, good performance status, ECOG status of 0 or 1, ability to debulk majority of disease, unresected disease being not threatening, patients with low/intermediate risk disease and presence of symptoms from the primary tumor.
Presented by: Bradley C. Leibovich, MD, Mayo Clinic, Rochester, Minnesota
1. Flanigan RC et al. J Urol 2004
2. Pantuck et al. NEJM 2001
3. Choueiri TK et al. J Urol 2011
4. Heng DYC et al. European Urol 2014
5. Bindi B et al. J Urol 2018
6. Méjean A et al. NEJM 2018
7. Elting LS et al. Cancer 2006
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona